DESCRIPTION (taken from the application): In the hospital setting when patients with severe injuries resulting from trauma, burns, or major surgery contract bacterial infections a syndrome known as septic shock often develops. It is estimated that in the United States alone more than 100,000 deaths per year occur in this patient group and the overall costs due to morbidity and mortality are enormous. The immune systems -- both innate and acquired -- play major roles in the development of the septic shock syndrome. Although most of the recent focus has been on the response of the innate immune system we believe important links exist between the innate and acquired immune system in some patients. In the past decade major advances in our understanding of events leading to septic shock have occurred but translation of this information into new therapy has not been successful. However, some basic principles have been tentatively validated from clinical studies. For example the role of pro-inflammatory mediators or the principle of blocking endotoxin has been suggested by retrospective analyses or in limited clinical trials. One can look for many reasons to explain what seems to be continuing failure but it is our view that the complexity of interacting systems has not been sufficiently appreciated. A successful effort to provide new treatments must bridge several major gaps in our knowledge. To do this we propose the following: (1) To define the biochemical pathways leading to new gene expression during the course of the disease through the study of in vitro and in vivo models. The goal of these studies is to test new hypotheses in man and (2) To provide new tools for classifying patients with a specific emphasis on underlying genetic factors that may enhance or reduce susceptibility to the septic shock. To accomplish these goals we have assembled a team of basic and clinical scientists to bring to bear all of the major advances available in bioinformatics, genomics, proteomics and structural biology coupled with expertise in cellular and whole animal biology to analyze appropriate model systems so that the septic shock syndrome can be defined in terms of biochemical pathways within the immune system. These data will form the basis of further studies in appropriate clinical populations.